Project Summary/Abstract: Skin and soft tissue infections are a major public health threat. Exacerbating the problem has been the development of antibiotic resistant strains of bacteria. Like the hide of an animal, human skin creates a physical barrier between a person and its environment. The skin is also home to cells and molecules of the immune system that create an immunological barricade to infection. A critical component of the skin barrier are antimicrobial proteins- evolutionarily ancient immune effectors that maintain mutually-beneficial host-microbial relationships at multiple epithelial surfaces, such as the skin and the intestine. Recently, we discovered that proteins in the Resistin family (human Resistin and mouse RELM?) are antimicrobial and expressed by keratinocytes and by sebaceous glands - the oil producing glands of the skin. In addition to RELM?, there are innumerable proteins elaborated by sebaceous glands with unknown biochemical function. Little is understood about the role that bacteria play in regulating the expression of these proteins. We thus wanted to identify other genes expressed by the sebaceous gland that might, 1) play a role in host defense and 2) modulate the skin microbiome. Using whole transcriptome sequencing (RNA-seq), we compared the expression profile of sebocytes treated with lipopolysaccharide (LPS) to sebocytes treated with a vehicle control. We were surprised to find that 4 members of the small proline rich family (gene name SPRR) were upregulated by LPS. SPRR proteins also have structural features similar to other described antimicrobial proteins. Our preliminary data indicate that SPRR1A and SPRR2A proteins can kill skin commensals in vitro. In this proposal we will utilize an array of in vitro and in vivo techniques to: (Aim 1) determine whether SPRR1A can kill bacterial pathogens, (Aim 2) delineate how SPRR1 proteins are secreted from skin, and (Aim 3) determine the physiologic function of SPRR2A in skin. These studies will help us understand how the sebaceous gland contributes to cutaneous host defense. My long-term career goal is to develop an independent research program that investigates host defense at the skin surface. After completing MD/PhD and Dermatology training at Johns Hopkins, I was recruited to UT Southwestern to train as a post-doctoral fellow in the lab of Lora Hooper, Ph.D, an internationally recognized leader in mechanistic studies of the host/microbe interface and the characterization of antimicrobial proteins in the gastrointestinal tract. During my tenure in the Hooper lab, I have expanded the focus of the lab to include skin. This career develop award will support my final years in this unique training environment and give me the opportunity to gain new skills in: 1) cellular trafficking biochemistry and 2) bacterial genomics. I have created a mentorship team of scientists to help fill these gaps in my training, Sandra Schmid Ph.D., Heidi Kong M.D., and Julia Segre Ph.D. Through the completion of these aims, I will create a fully independent research platform, able to generate novel therapeutic solutions for skin infections and inflammatory skin diseases.